6-32581554-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002124.4(HLA-DRB1):c.652+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 10)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: HLA-DRB1 NM_002124.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001678
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.828

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa. It is encoded by 6 exons. Exon one encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain; and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 6-32581554-C-T is Benign according to our data. Variant chr6-32581554-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2656459.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-DRB1	NM_002124.4	c.652+3G>A		splice_donor_region_variant, intron_variant		ENST00000360004.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-DRB1	ENST00000360004.6	c.652+3G>A		splice_donor_region_variant, intron_variant			NM_002124.4	P1

Frequencies

GnomAD3 genomes AF: 0.000103 AC: 8 AN: 77540 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.000235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000269

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00333 AC: 597 AN: 179480 Hom.: 5 AF XY: 0.00329 AC XY: 325 AN XY: 98676

Gnomad AFR exome AF: 0.00355

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.00819

Gnomad FIN exome AF: 0.00299

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.000491 AC: 492 AN: 1001462 Hom.: 6 Cov.: 17 AF XY: 0.000622 AC XY: 315 AN XY: 506456

Gnomad4 AFR exome AF: 0.000473

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000794

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.000326

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000467

GnomAD4 genome AF: 0.000103 AC: 8 AN: 77616 Hom.: 0 Cov.: 10 AF XY: 0.000188 AC XY: 7 AN XY: 37288

Gnomad4 AFR AF: 0.000234

Gnomad4 AMR AF: 0.000157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000421

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000269

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00275 Hom.: 64

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

HLA-DRB1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34309628; hg19: chr6-32549331;